Effect of the solvent-dependent conformational system of hydroxyureas on predicted vs. observed log P.
Calculated and observed log P values are reported and compared with in vivo and in vitro biological action (L1210 leukemia ILS % and ribonucleotide reductase ID50) for hydroxyurea, the 1-N methyl and ethyl, and the 3-N ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, phenyl, and p-chlorophenyl analogues. The log P values were calculated via the method of Hansch and Leo from literature f values and the observed log P values were obtained by direct determination after equilibration between octanol and water. Calculations of log P for hydroxyurea were found to be appreciably more hydrophilic than the values obtained experimentally. Differences in calculated and observed log P (delta log P) for the substituted analogues were lowest with the 1-N and the bulky 3-N substituents and greatest with the 3-N-substituted straight-chain analogues (delta log P = 0.70). Different structural species were observed by infrared spectroscopy in dry octanol vs. octanol after water equilibration and drying, and this is proposed as due to changes in conformational equilibrium in the hydroxyurea systems. Differences between calculated and observed log P are explained via the stabilization of internally hydrogen-bonded conformers in the case of 1-N or bulky 3-N analogues or destabilization of various conformers allowing maximal interactions with solvent or water which is the case with straight chain 3-N analogues.


Meta-analysis of qualitative studies: a tool for reviewing qualitative research findings in psychotherapy.
This article focuses on the presentation of qualitative meta-analysis as a method for reviewing qualitative studies. Qualitative meta-analysis is an attempt to conduct a rigorous secondary qualitative analysis of primary qualitative findings. Its purpose*to provide a more comprehensive description of a phenomenon and an assessment of the influence of the method of investigation on findings*is discussed. The distinctive features of conducting meta-analysis approaches are presented. Several considerations important for conducting qualitative meta-analysis are also discussed. The author uses examples of the first experiences attempted with qualitative meta-analysis in the field of psychotherapy research.


Analysis of flow motion by the laser Doppler technique in patients with peripheral arterial occlusive disease.
Laser Doppler flux was measured at the forefoot in 12 healthy subjects and in 36 patients with different degrees of ischemia due to peripheral arterial occlusive disease. Two characteristic patterns of flow motion waves were observed: Large waves with a mean amplitude of 0.77 +/- 0.4 arbitrary units and a mean frequency of 3.03 +/- 1.0 c/min (0.051 +/- 0.02 Hz) and small waves with a mean amplitude of 0.21 +/- 0.1 arbitrary units and a mean frequency of 21.7 +/- 4.2 c/min (0.362 +/- 0.07 Hz). The prevalence of large waves tended to decrease with more advanced ischemia, whereas small waves occurred almost exclusively in ischemia and most frequently in severe cases. Large flow motion waves were enhanced during reactive hyperemia after arterial occlusion or appeared after peak flux had been reached. Time to peak flux or to vasomotion were reliable parameters for characterizing skin ischemia. The previously undescribed small flow motion waves might represent a compensatory mechanism involved in pathophysiology of ischemia.


Colitis as the Initial Presentation of Eosinophilic Granulomatosis with Polyangiitis.
A male patient in his early sixties with recurrent diarrhea was transferred to our hospital. The patient did not have any pulmonary or upper respiratory symptoms. He was noted to have peripheral eosinophilia. Further workup revealed a negative antineutrophilic cytoplasmic antibody titer but a positive myeloperoxidase antibody and positive proteinase 3 antibodies. A colon biopsy also revealed eosinophilic-rich granulomas in the mucosa, confirming a diagnosis of eosinophilic granulomatosis with polyangiitis. On cardiac imaging, eosinophilic myocarditis was also discovered. To treat active severe EGPA, the patient received high-dose corticosteroids and intravenous cyclophosphamide. The occurrence of gastrointestinal involvement as an initial manifestation of eosinophilic granulomatosis with polyangiitis is infrequent, emphasizing the significance of its recognition. This case underscores the importance of identifying and diagnosing such atypical presentations to facilitate timely and appropriate management.


PPARα Agonist Fenofibrate Enhances Cancer Vaccine Efficacy.
Reducing metabolic stress within the tumor microenvironment (TME) could be essential for improving the efficacy of cancer immunotherapy. Using a mouse model of melanoma, we show here that appropriately timed treatment with the PPARα agonist fenofibrate improves the ability of a T cell-inducing cancer vaccine to delay tumor progression. Fenofibrate reduced the use of glucose by tumor and stromal cells in the TME and promoted the use of fatty acids for their metabolic needs. The glucose within the TME was in turn available for use by vaccine-induced tumor-infiltrating CD8+ T cells, which improved their ability to slow tumor progression. Early fenofibrate treatment 3 days after vaccination improved functions of circulating CD8+ T cells but failed to significantly affect tumor-infiltrating lymphocyte (TIL) metabolism or decrease tumor progression. In contrast, delaying treatment until day 5 after vaccination modified TIL metabolism and augmented the vaccine's ability to slow tumor progression. In summary, our findings reveal that a PPARα agonist can increase the efficacy of a cancer vaccine by reprogramming cells within tumors to increase fatty acid metabolism, providing T cells access to glucose in the TME. SIGNIFICANCE: These findings suggest that metabolic manipulations using already approved drugs may offer an easy pathway to increase the efficacy of vaccines against solid tumors.


Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma.
This randomized, controlled trial assessed the efficacy of transarterial Lipiodol (Lipiodol Ultrafluide, Laboratoire Guerbet, Aulnay-Sous-Bois, France) chemoembolization in patients with unresectable hepatocellular carcinoma. From March 1996 to October 1997, 80 out of 279 Asian patients with newly diagnosed unresectable hepatocellular carcinoma fulfilled the entry criteria and randomly were assigned to treatment with chemoembolization using a variable dose of an emulsion of cisplatin in Lipiodol and gelatin-sponge particles injected through the hepatic artery (chemoembolization group, 40 patients) or symptomatic treatment (control group, 40 patients). One patient assigned to the control group secondarily was excluded because of unrecognized systemic metastasis. Chemoembolization was repeated every 2 to 3 months unless there was evidence of contraindications or progressive disease. Survival was the main end point. The chemoembolization group received a total of 192 courses of chemoembolization with a median of 4.5 (range, 1-15) courses per patient. Chemoembolization resulted in a marked tumor response, and the actuarial survival was significantly better in the chemoembolization group (1 year, 57%; 2 years, 31%; 3 years, 26%) than in the control group (1 year, 32%; 2 years, 11%; 3 years, 3%; P =.002). When adjustments for baseline variables that were prognostic on univariate analysis were made with a multivariate Cox model, the survival benefit of chemoembolization remained significant (relative risk of death, 0.49; 95% CI, 0.29-0.81; P =.006). Although death from liver failure was more frequent in patients who received chemoembolization, the liver functions of the survivors were not significantly different. In conclusion, in Asian patients with unresectable hepatocellular carcinoma, transarterial Lipiodol chemoembolization significantly improves survival and is an effective form of treatment.


Multidimensional Aspects of de qi Sensations in MASS and ASQ Assessment: A Pilot Study.
Background. De qi comprises varied senses depending on the individual. No single method can yet fully measure the multiple dimensions of de qi adequately. Objective. We examined the advantages of implementing multiple questionnaires for de qi measurement. Methods. Fourteen participants completed a preacupuncture questionnaire regarding their perception toward acupuncture treatment. After acupuncture stimulation at the HT7 point, de qi sensations were measured by MASS and ASQ. In groups with different levels of expectation, we compared the subtotal scores of each phase in the ASQ, as well as the VAS de qi intensity and MASS index using Kruskal-Wallis test. For the structural comparison of questionnaires, we first performed Spearman's rank correlation test between the scores of individual descriptors in MASS and ASQ. The subtotal scores of each phase in ASQ was compared with VAS de qi intensity and MASS index. Results. The subtotal score of the manipulation phase in ASQ strongly correlated with the VAS score of de qi intensity (Spearman's ρ = 0.654, p = 0.011) and MASS index (Spearman's ρ = 0.488, p = 0.076). MASS and ASQ showed strong correlations in certain analogous descriptors. Unpleasant perceptions toward acupuncture treatment did not significantly correlate with overall de qi intensity. Conclusions. De qi sensations in acupuncture treatment have multidimensional aspects. Intensity of stimulation, ASQ, and MASS index assess somewhat restricted aspects of de qi. Those questionnaires have exclusive differences of sets in spite of their strong intersections. Use of multiple questionnaires may enable a more comprehensive understanding of de qi properties and the elicitation of relevant construction in de qi features of acupuncture.


[The study on differential gene expression profiling in pulmonary tissue of rats exposed to silica early].
To study the differential gene expression profiling of rats exposed to silica using the normal rats as control. Animal models were established using intratracheal injection of the lung and 22 107 genes were screened in the differential expression profiling of silicosis by using oligonucleotide bead array. Differential expression profiling data were analyzed by using DAVID bioinformation software. Totally 1567 differentially expressed genes were identified in lungs of silica exposed rats including 765 up-regulated genes and 802 down-regulated genes as compared to the normal controls. Among 406 annotated genes in KEGG pathways, 204 genes and 11 pathways were up-regulated as well as 202 genes and 3 pathways were down-regulated in silica exposed rats. All 1567 genes are involved in the formation of silicosis. The differential gene expression profile of silicosis describes the general changes in the gene expressions in silicosis at transcriptional level. Further analysis of the identified genes might help reveal the molecular mechanism of pulmonary fibrosis induced by silica.


Changes in the importance of quality of life domains after cancer diagnosis.
The aim of this study was to describe what domains in quality of life were considered most or least important by patients with newly diagnosed cancer and in what way the domains of importance changed during a 9-month period. We also analysed the impact of selected demographic variables on the important domains. The Ferrans' and Powers' Quality of Life Index was used to measure quality of life. As this index consists of one section measuring the importance of various domains of life, information about changing standards was available. The study sample consisted of 131 adult patients recently diagnosed with different cancers. The whole sample filled in the questionnaire once, while part of the sample (n = 41) filled it in four times during a 9-month period. Items related to family matters were rated as most important, while faith in God was reported to be of least importance. The patients fluctuated somewhat in terms of what was most important to them during the study period. Overall, the most unstable items tended to be less important over time. In addition, results showed significant differences in the importance of quality of life domains according to gender, age, educational level and cohabitation.


Unilateral COVID-19-associated vasculitic central retinal vein occlusion: phlebitis with subhyaloid, intraretinal and subretinal hemorrhages.
To describe unilateral vasculitic central retinal vein occlusion (CRVO) in a young adult whose vision problems preceding system symptoms of COVID-19 infection. Observational clinical case report. A 39-year-old immunocompetent male without prior ocular disease presented for vitreoretinal care complaining of decreasing vision in his right eye for two weeks. Headaches, pharyngitis and coughing began four days after his visual symptoms. COVID-19 testing was negative prior to initial vitreoretinal evaluation and positive afterward. Dilated and tortuous major retinal veins in his right eye had prominent perivascular sheathing. A large subhyaloid hemorrhage spanned the macula. Subretinal hemorrhages were present in areas of sheathing and diffuse nerve fiber layer hemorrhages were arrayed in the distribution of the radial peripapillary capillary plexus. Laboratory tests for inflammatory diseases were negative. The patient was hospitalized for COVID-19 pneumonia a few days after his initial vitreoretinal evaluation. Pars plana vitrectomy was performed for persistent subhyaloid hemorrhage eight weeks after his hospitalization. The visual acuity in the patient's right eye improved from CF to 20/30 post-operatively. The patient's findings are consistent with an atypical CRVO which we hypothesize to be of vasculitic origin because of prominent associated retinal phlebitis and venous sheathing. Concomitant subhyaloid, nerve fiber layer and subretinal hemorrhages involved the superficial and deep retinal vascular complexes. The patient's COVID-19-related hospitalization and systemic management delayed surgical management of his subhyaloid hemorrhages but a good visual result was achieved despite persistence of macular preretinal blood for three months.


Isocitrate Dehydrogenase Mutations in Glioma: From Basic Discovery to Therapeutics Development.
Isocitrate dehydrogenase (IDH) is a key rate-limiting enzyme in the Krebs cycle that plays an important role in energy metabolism. In recent years, it has been found that IDH mutations are closely related to the occurrence and development of glioma, and it is a notable potential therapeutic target. First, IDH mutations can produce high levels of 2-hydroxyglutaric acid (2-HG), thereby inhibiting glioma stem cell differentiation. At the same time, IDH mutations can upregulate vascular endothelial growth factor (VEGF) to promote the formation of the tumor microenvironment. In addition, IDH mutations can also induce high levels of hypoxia-inducible factor-1α (HIF-1α) to promote glioma invasion. Ultimately, these changes will lead to the development of glioma. Currently, a large number of IDH inhibitors and vaccines have entered clinical trials, representing progress in the treatment of glioma patients.


N-linked glycosylation of AtVSR1 is important for vacuolar protein sorting in Arabidopsis.
Vacuolar sorting receptors (VSRs) in Arabidopsis mediate the sorting of soluble proteins to vacuoles in the secretory pathway. The VSRs are post-translationally modified by the attachment of N-glycans, but the functional significance of such a modification remains unknown. Here we have studied the role(s) of glycosylation in the stability, trafficking and vacuolar protein transport of AtVSR1 in Arabidopsis protoplasts. AtVSR1 harbors three complex-type N-glycans, which are located in the N-terminal 'PA domain', the central region and the C-terminal epidermal growth factor repeat domain, respectively. We have demonstrated that: (i) the N-glycans do not affect the targeting of AtVSR1 to pre-vacuolar compartments (PVCs) and its vacuolar degradation; and (ii) N-glycosylation alters the binding affinity of AtVSR1 to cargo proteins and affects the transport of cargo into the vacuole. Hence, N-glycosylation of AtVSR1 plays a critical role in its function as a VSR in plants.


[Merkel cell carcinoma: a report of two cases].
We present two cases of Merkel cell carcinoma (also called cutaneous neuroendocrine carcinoma) and review the relevant literature. This is a rare skin tumor that is very aggressive, with a great tendency to local recurrence and rapid metastatic spread to regional lymph nodes as well as hematogeneous dissemination. We discuss the usefulness of different imaging modalities in determining the extension of disease and in patient follow-up.


A study of personality factors and interaction in 4th-year dental students and their teachers.
No previous investigation has considered dental student and teaching staff opinions on their relationship with each other. In a day when students are increasingly asked for feedback on the quality of teaching by staff, such investigations are of particular interest. This exploratory study was designed to compare the personality characteristics of a clinical year of dental students with those of the teaching staff they most frequently encountered, and to investigate these factors for possible associations with the quality of perceived teaching-learning interaction between the 2 groups. A complete 4th year of dental students (n = 87), and those teachers whom they met regularly (n = 80), were asked to participate. Subjects completed a form of the Myers-Briggs personality questionnaire simplified for use in education, and were asked to assess their relationship with persons in the other group. All the students and 75% of the staff, after follow-up, returned usable data. There was close similarity between staff and student personality profiles, and perception of working relationships by both groups was largely independent of personality factors and temperament. There were differences in staff perception of their relationship with extrovert and introvert students. Students showed minor differences in their perception of staff relationships with respect to two other personality factors. These findings indicate a substantial similarity between staff and students, and suggest a mature and stable relationship between people in the 2 groups.


Potential signaling pathway of hypoxia-inducible factor in lung cancer and its gene polymorphism with lung cancer risk.
Lung cancer is becoming the leading cause of cancer death worldwide with highest morbidity and mortality, and knowing the pathogenesis and signaling pathway is very important and advances in the diagnosis and treatment of the disease are urgently needed. Gene polymorphism was reported to be associated with the lung cancer risk. We reviewed the potential signaling pathway of hypoxia-inducible factor in lung cancer and conducted a meta-analysis to explore its gene polymorphism with lung cancer risk. In the meta-analysis, hypoxia-inducible factor-1α (HIF-1α) G1790A A allele, AA genotype and GG genotype were associated with lung cancer risk (A allele: OR = 2.31, 95% CI: 1.77-3.02, p < 0.00001; AA genotype: OR = 4.52, 95% CI: 2.31-8.83, p < 0.0001; GG genotype: OR = 0.45, 95% CI: 0.33-0.63, p < 0.00001). Furthermore, HIF-1α C1772 TT genotype and CC genotype were associated with lung cancer risk, but the T allele was not. In conclusion, HIF-1α G1790A A allele, AA genotype and GG genotype, HIF-1α C1772 TT genotype and CC genotype were associated with lung cancer risk. However, more studies should be performed to confirm it.


Clinical trial of intra-articular injection of sodium hyaluronate in patients with osteoarthritis of the knee.
A multi-centre randomized, double-blind, parallel-group clinical trial was carried out in 63 patients with osteoarthritis of the knee to compare the efficacy and tolerability of a course of intra-articular injections of 20 mg sodium hyaluronate with a similar course of injections of placebo. Treatment consisted of up to 11 injections over a 23-week period. Evaluation was by means of subjective symptom and activity assessments, serially during the course of treatment and also 25 weeks thereafter. Ten patients (5 of 30 on active treatment; 5 of 33 on placebo) were withdrawn prematurely. Pain on movement, assessed by visual analogue scale (VAS) showed statistically significant (p less than 0.05 to p less than 0.0001) reductions in mean scores throughout the first 11 weeks of treatment with sodium hyaluronate but smaller, non-significant, reductions with placebo treatment. The difference between treatments was significant (p less than 0.05) at 5 weeks. Pain at rest, also assessed by VAS, showed little change in mean scores with placebo but with sodium hyaluronate there was a progressive reduction which was significant (p less than 0.01) throughout the period from 5 to 23 weeks. The difference between sodium hyaluronate and placebo was significant (p less than 0.05 to p less than 0.002) at Weeks 5, 11, 15, 19 and 23. 'Activities of daily living' were assessed using a standard scale. There were small improvements with both treatments, significant at some assessments and somewhat greater with sodium hyaluronate than placebo, but there were no statistically significant differences between the groups.(ABSTRACT TRUNCATED AT 250 WORDS)


N-cadherin functions as a growth suppressor in a model of K-ras-induced PanIN.
Cadherin subtype switching from E-cadherin to N-cadherin is associated with the epithelial-to-mesenchymal transition (EMT), a process required for invasion and dissemination of carcinoma cells. We found that N-cadherin is expressed in human and mouse pancreatic intraepithelial neoplasia (PanIN), suggesting that N-cadherin may also have a role in early-stage pancreatic cancer. To investigate the role of N-cadherin in mouse PanIN (mPanIN), we simultaneously activated oncogenic K-ras(G12D) and deleted the N-cadherin (Cdh2) gene in the murine pancreas. Genetic ablation of N-cadherin (N-cad KO) caused hyperproliferation, accelerated mPanIN progression, and early tumor development in K-ras(G12D) mice. Decreased E-cadherin and redistribution of β-catenin accompanied the loss of N-cadherin in pancreatic ductal epithelial cells (PDEC). Nuclear accumulation of β-catenin and its transcription co-activator Tcf4 led to activation of Wnt/β-catenin target genes. Unexpectedly, loss of N-cadherin in the K-ras(G12D) model resulted in increased mPanIN progression and tumor incidence. These in vivo results demonstrate for the first time that N-cadherin functions as a growth suppressor in the context of oncogenic K-ras.


Dentists' Utilization of Caries Risk Assessment and Individualized Caries Prevention Methods in Pediatric Patients in Saudi Arabia.
The first step in any complete oral health care plan for a child is a thorough caries risk assessment (CRA). This study aimed to investigate whether the practice dentists in Saudi Arabia's Western province do CRA methods and offer Individualized Caries Prevention (ICP) to their pediatric patients. Dentists in active clinical practice in the Western province of Saudi Arabia were the participants of this cross-sectional survey. The participants in this study were chosen using a simple random sampling technique. A self-administered, structured questionnaire was used to gather participants' responses. A majority (88.2%) of the dentists agreed that it is very important to practice CRA on a regular basis among their pediatric patients. About 67% of dentists employed Individualized Caries Prevention methods. No statistically significant correlation was observed between ICP and CRA factors, indicating that interventions primarily focused on patients' financial affordability. Dentists should encourage parents/caregivers to establish a dental home concept at the earliest, which includes CRA, education, and anticipatory guidance on the prevention of oral diseases.


Survival of avulsed permanent maxillary incisors in children following delayed replantation.
The purpose of this study was to identify the variables that significantly influenced the survival of incisors replanted after extended extra-alveolar duration at The Hospital for Sick Children, Toronto, Canada, between June 1988 and December 1993. Survival analysis was used to identify variables that significantly influence the retention of replanted incisor teeth. Survival was defined as the time that elapsed between the replantation of an avulsed incisor and the time it was finally lost. Information on 9 variables was collected for 38 patients (25 males; 13 females) and 52 replanted permanent maxillary incisors. The mean extra-alveolar duration for the sample was 123 min. The mean follow-up interval was 942 days (range: 364-2126 days). Incisors replanted with open apices had a significantly decreased survival compared with teeth with mature apices (P = 0.04; relative risk 4.2). There was also a significant association between increased survival and obturation of the root canal with gutta-percha and sealer (P = 0.006; relative risk 10.0). A trend towards improved survival of replanted incisors was found for children older than 11 years old at the time of replantation (P = 0.09; relative risk 2.8). These results are consistent with previous studies and may assist clinicians and parents in the decision-making process associated with the management of avulsed teeth in children.


Overexpression of ZBP-89, a zinc finger DNA binding protein, in gastric cancer.
ZBP-89 is a Krüppel-type zinc finger protein that binds to the gastrin EGF response element (gERE). Sp1 binds to the same DNA element and transactivates gastrin promoter activity, whereas ZBP-89 competes for Sp1 binding and prevents EGF induction. Both transcription factors mediate growth factor signals originating from the EGF receptor and thus were studied in normal and neoplastic tissues or cell lines. When compared to normal tissue from the same patient, ZBP-89 protein expression was increased in neoplastic tissue from the stomach antrum and in malignant cell lines. RT-PCR analysis of ZBP-89 mRNA correlated with protein overexpression. Immunocytochemical studies confirmed that ZBP-89 expression is elevated in neoplastic tissue and chronic gastritis, whereas Sp1 expression was nearly unchanged. These results suggest that the transcription factor ZBP-89, like Sp1, may be a marker for neoplastic transformation in some gastric cancers.


Environmental contamination and personal protective equipment contamination with SARS-CoV-2 virus in a real-life clinical setting.
The importance of SARS-CoV-2 transmission via contact routes and its stability on surfaces is becoming increasingly recognised. There is ongoing concern that patients can become infected through person-to-person spread and environment-to-person spread. This study assessed whether SARS-CoV-2 viral RNA can be detected in the environment either on staff members' personal protective equipment (PPE), on high-touch surfaces or around the bedspace of COVID-19-positive patients in a range of different ward settings to evaluate if there was any contamination of these. Results showed all PPE and high-touch surface swabs were negative. All swabs taken in the negative-pressure room where aerosol-generating procedures (AGPs) were being undertaken detected viral RNA (5/5 positive), whereas there was minimal contamination in the intensive therapy unit (1/5 positive) and none detected in the cohort bay. These findings would be consistent with the understanding that areas where AGPs are regularly performed are at higher risk of environmental contamination.


Fused Bicyclic Heteroaryl Compounds as NLRP3 Inhibitors for Treating Asthma or COPD.
Provided herein are novel fused bicyclic heteroaryl compounds as NLRP3 inhibitors, pharmaceutical compositions, use of such compounds in treating asthma or COPD and processes for preparing such compounds.


Implant stability during initiation and resolution of experimental periimplantitis: an experimental study in the dog.
Histologic studies have demonstrated the possibility to reestablish direct bone-implant contacts after ligature-induced periimplantitis. The influence of the reosseointegration on the stability of implants is not known. The aim of the present investigation was to study bone tissue and associated implant stability alterations that occurred during induction and resolution of periimplantitis using resonance frequency analysis (RFA), radiography, and histology. Three implants with smooth (turned) or roughened (SLA) surfaces were placed in each side of the edentulous mandible of four dogs. Experimental periimplantitis was induced for 3 months. Five weeks later, the animals were treated with antibiotics and surgical therapy and were followed for another 6 months. Periapical radiographs and RFA were used to evaluate marginal bone levels and implant stability throughout the study period. After termination, the tissue-implant interface was evaluated by light microscopy in ground sections. There was a linear relationship between radiographic and RFA findings because continuous loss of marginal bone and a decrease in implant stability were observed for both implant surfaces during the periimplantitis period. Antibiotic treatment and surgical therapy resulted in some reosseointegration, which was more marked for the SLA surface. The resonance frequency values corresponded well to the histometric measurements because reosseointegration resulted in an increase in implant stability. The findings from the present study indicate a linear relationship between marginal bone level and resonance frequency value. It is suggested that the RFA technique is sensitive and may be used to detect even a minor change in the level of bone-implant contact.


Multimodality Imaging in the Detection of Ischemic Heart Disease in Women.
Women with coronary artery disease tend to have a worse short and long-term prognosis relative to men and the incidence of atherosclerotic cardiovascular disease is increasing. Women are less likely to present with classic anginal symptoms when compared with men and more likely to be misdiagnosed. Several non-invasive imaging modalities are available for diagnosing ischemic heart disease in women and many of these modalities can also assist with prognostication and help to guide management. Selection of the optimal imaging modality to evaluate women with possible ischemic heart disease is a scenario which clinicians often encounter. Earlier modalities such as exercise treadmill testing demonstrate significant performance variation in men and women, while newer modalities such as coronary CT angiography, myocardial perfusion imaging and cardiac magnetic resonance imaging are highly specific and sensitive for the detection of ischemia and coronary artery disease with greater parity between sexes. Individual factors, availability, diagnostic performance, and female-specific considerations such as pregnancy status may influence the decision to select one modality over another. Emerging techniques such as strain rate imaging, CT-myocardial perfusion imaging and cardiac magnetic resonance imaging present additional options for diagnosing ischemia and coronary microvascular dysfunction.


Luminescent terpyridine appended geminal bisazide and bistriazoles: multinuclear Pt(II) complexes and AIPE-based DNA detection with the naked eye.
We report square planar Pt(ii) complexes as luminescent biosensors for DNA detection in solution. The sensing is attributed to the aggregation induced bright red photoluminescence (AIPE) of the complexes in the presence of DNA that can be seen with the naked eye using only a 360 nm light source. Terpyridine appended luminescent geminal bistriazoles (L1-L4, from geminal bisazide A through azide-alkyne 'click' cycloaddition) with versatile chelating sites were explored for metal coordination and reaction with Pt(dmso)2Cl2 yielding tetranuclear and dinuclear complexes of Pt(ii) with different N∩N ligand environments. Thermally stable gem-bisazide and bistriazoles are hardly reported in the literature and this is the first report of terpyridine appended geminal bisazide and bistriazoles.


A morphometric study of foetal and newborn cardiac growth in the horse.
A morphometric study of hearts in 81 equine foetuses, ranging in age from 190 to 330 days of foetal age, and in 26 newborn foals is reported. The mean weight, external dimensions, ventricular wall thickness and circumference of the atrio-ventricular orifice were measured. Features of the main associated vessels of the heart were also recorded. All cardiac measurements of foetuses increased linearly throughout the latter half of pregnancy and were highly correlated with foetal age. This linear growth pattern was also found in the parameters of the associated arterial trunks. The ratio of the right ventricular weight to the total ventricular weight in the equine foetuses increased gradually from 0.27 (Day 190) to 0.34 (full term), but in newborn foals, this ratio began to decrease soon after birth, declining from 0.32 to 0.28 by 11 days of age. The interventricular septum was thickest followed by the right ventricular wall, and the left ventricular wall was thinnest during the period of gestation studied. The right ventricle was 3.2 per cent to 31.5 per cent thicker than the left ventricle.


Long-Term Outcomes of Transvenous Lead Extraction: A Comparison in Patients with or without Infection from the Italian Region with the Oldest Population.
The gold standard for the treatment of cardiac implantable electronic devices (CIEDs)-related infection and lead malfunction is transvenous lead extraction (TLE). To date, the risk of mortality directly related to TLE procedures is relatively low, but data on post-procedural and long-term mortality are limited, even more in the aging population. Consecutive patients with CIEDs who underwent TLE were retrospectively studied. The primary outcome was the endpoint of death, considering independent predictors of long-term clinical outcomes in the TLE aging population comparing patients with and without infection. One hundred nineteen patients (male 77%; median age 76 years) were included in the analysis. Eighty-two patients (69%) documented infection, and thirty-seven (31%) were extracted for a different reason. Infected patients were older (80 vs. 68 years, p-value > 0.001) with more implanted catheters (p-value < 0.001). At the last follow-up (FU) available (median FU 4.1 years), mortality reached 37% of the patient population, showing a statistically significant difference between infected versus non-infected groups. At univariable analysis, age at TLE, atrial fibrillation, and anemia remained significant correlates of mortality; at multivariable analysis, only patients with anemia and atrial fibrillation have a 2.3-fold (HR 2.34; CI 1.16-4.75) and a 2.5-fold (HR 2.46; CI 1.33-4.54) increased rate of death, respectively. Our long-term data showed that aging patients who underwent TLE for CIED-related infection exhibit a high mortality risk during a long-term follow-up, potentially leading to a rapid and effective procedural approach in this patient population.


Effect of weak acid preservatives on growth of bakery product spoilage fungi at different water activities and pH values.
Inhibition of spoilage organisms from bakery products by weak acid preservatives in concentrations of 0%, 0.003%, 0.03% and 0.3% (w/v) was investigated experimentally on a substrate media with water activity (a(w)) and pH ranging from sourdough-fermented acidic rye bread to alkaline intermediate moisture sponge cake types (a(w) 0.80-0.95, pH 4.7-7.4). Initially, rye bread conditions (a(w) 0.94-0.97 and pH 4.4-4.8) in combination with calcium propionate were investigated. Results showed that the highest concentration of propionate (0.3%) at all conditions apart from high a(w) (0.97) and high pH (4.8) totally inhibited fungal growth for a 2-week period, with the exception of Penicillium roqueforti, Penicillium commune and Eurotium rubrum. Characteristically for the major spoiler of rye bread, P. roqueforti, all three isolates tested were stimulated by propionate and the stimulation was significantly enhanced at high water activity levels. The effect of propionate on production of secondary metabolites (mycophenolic acid, rugulovasine, echinulin, flavoglaucin) was also studied, and variable or isolate dependent results were found. Subsequently, a screening experiment representing a wider range of bakery products was conducted using calcium propionate, potassium sorbate and sodium benzoate. The obtained data was modelled using survival analysis to determine 'spoilage-free time' for the fungi. At the low a(w) level (0.80) only Eurotium species grew within the test period of 30 days. Higher water activity levels as well as higher pH values decreased spoilage-free times of the fungi. The preservative calcium propionate was less effective than potassium sorbate and sodium benzoate.


Intracellular processing, glycosylation, and cell surface expression of human metapneumovirus attachment glycoprotein.
The biosynthesis and posttranslational processing of human metapneumovirus attachment G glycoprotein were investigated. After pulse-labeling, the G protein accumulated as three species with molecular weights of 45,000, 50,000, and 53,000 (45K, 50K, and 53K, respectively). N-Glycosidase digestion indicated that these forms represent the unglycosylated precursor and N-glycosylated intermediate products, respectively. After an appropriate chase, these three naive forms were further processed to a mature 97K form. The presence of O-linked sugars in mature G protein was confirmed by O-glycanase digestion and lectin-binding assay using Arachis hypogaea (peanut agglutinin), an O-glycan-specific lectin. In addition, in the O-glycosylation-deficient cell line (CHO ldlD cell), the G protein could not be processed to the mature form unless the exogenous Gal and GalNAc were supplemented, which provided added evidence supporting the O-linked glycosylation of G protein. The maturation of G was completely blocked by monensin but was partially sensitive to brefeldin A (BFA), suggesting the O-linked glycosylation of G initiated in the trans-Golgi compartment and terminated in the trans-Golgi network. Enzymatic deglycosylation analysis confirmed that the BFA-G was a partial mature form containing N-linked oligosaccharides and various amounts of O-linked carbohydrate side chains. The expression of G protein at the cell surface could be detected by indirect immunofluorescence staining assay. Furthermore, cell surface immunoprecipitation displayed an efficient intracellular transport of G protein.


Impacts of late Quaternary environmental change on the long-tailed ground squirrel (Urocitellus undulatus) in Mongolia.
Impacts of Quaternary environmental changes on mammal faunas of central Asia remain poorly understood due to a lack of geographically comprehensive phylogeographic sampling for most species. To help address this knowledge gap, we conducted the most extensive molecular analysis to date of the long-tailed ground squirrel (Urocitellus undulatus Pallas 1778) in Mongolia, a country that comprises the southern core of this species' range. Drawing on material from recent collaborative field expeditions, we genotyped 128 individuals at 2 mitochondrial genes (cytochrome b and cytochrome oxidase I; 1 797 bp total). Phylogenetic inference supports the existence of two deeply divergent infraspecific lineages (corresponding to subspecies U. u. undulatus and U. u. eversmanni), a result in agreement with previous molecular investigations but discordant with patterns of range-wide craniometric and external phenotypic variation. In the widespread westerneversmanni lineage, we recovered geographically-associated clades from the: (a) Khangai, (b) Mongolian Altai, and (c) Govi Altai mountain ranges. Phylogeographic structure in U. u. eversmanni is consistent with an isolation-by-distance model; however, genetic distances are significantly lower than among subspecies, and intra-clade relationships are largely unresolved. The latter patterns, as well as the relatively higher nucleotide polymorphism of populations from the Great Lakes Depression of northwestern Mongolia, suggest a history of range shifts into these lowland areas in response to Pleistocene glaciation and environmental change, followed by upslope movements and mitochondrial lineage sorting with Holocene aridification. Our study illuminates possible historical mechanisms responsible for U. undulatus genetic structure and contributes to a framework for ongoing exploration of mammalian response to past and present climate change in central Asia.


[Pelviscopic surgery in gynaecology (author's transl)].
Surgery of the fallopian tubes has today developed into pelviscopic surgery. The development of suitable instruments such as the tube set, a new endocoagulation method were prerequisites for this development. Operative therapeutic pelviscopic surgery is a development past laparotomy. It is now possible to treat adhesions in the abdomen with this method, to coagulate and divide fallopian tubes for sterilization, to aspirate ovarian cysts and resect walls of ovarian cysts, to coagulate endometriosis and to perform salpingolysis and salpingostomy. In selected cases ovariectomy and myomectomy are possible through the pelviscope. Tables and statistics on 3300 pelviscopies are presented. The indications are discussed. The use of pelviscopy following previous laparotomy (1831 cases) is discussed. The complication rate was 1.10% without death, without injury to large vessels, without embolic phenomenon. The operative risk is therefore less than that of laparotomy. The operative therapeutic pelviscopy can replace the classical laparotomy in about 25% of the cases. For the operation of tubal infertility, a laparotomy is eliminated in about 80% of the cases.


Role of elongation factor 1 in the translational control of rodent brain protein synthesis.
The translational control of protein synthesis during early postnatal neural development and aging was examined in the mouse and the rat. The activity of brain elongation factor 1 (bEF-1) was found to decrease exponentially with age and to decline parallel to the age-dependent decrease in total protein synthesis in both rodents. This decrement in bEF-1 activity fell within the range of reported age-related decreases in protein synthesis in in vitro systems. The factor was present in multiple forms; the lighter species predominated in older animals, whereas the young light form apparently disappeared with increasing age, and was replaced by other arising from the heavy form. Elongation factor 1 derived from young brains functioned as a rate-limiting component in polypeptide synthesis in previously saturated adult systems. The data suggest that bEF-1 has an important modulatory effect on total brain protein synthesis.


Fluorescence-suppressed Raman technique for quantitative analysis of protein solution using a micro-Raman probe, the shifted excitation method, and partial least squares regression analysis.
A practical Raman analyzing technique with suppression of the strong fluorescent background in order to obtain quantitative information is proposed in the present study. The technique is based on the shifted excitation method and partial least squares regression (PLSR) analysis. The Raman system consists of a single Raman spectrometer, a background-free electrically tunable Ti:Sapphire laser (BF-ETL), and a micro-Raman probe (MRP). The system allows one to obtain reliable shifted excitation Raman spectra with a simple operation. The PLSR analysis successfully provides quantitative information from the obtained spectra with the suppression of random noise including photon shot noise. The present study demonstrates that the technique is effective for extracting quantitative information concealed behind a fluorescent background that is more than 200 times stronger than the Raman signal.


Bridging the gap: liaison between nursing education and nursing service.
The integration of nursing education and nursing practice is a problem of both the British system and the North American system. Liaison between educators and service staff is often difficult. Between December 1977 and December 1978 informal observations were made at a London teaching hospital and three Scottish colleges of nursing, to determine how much liaison actually occurs between education and service. Some organizational literature gives pointers to ways education and service may be integrated. The British and North American systems are contrasted to highlight some of the differences and similarities of the systems. The integration of theory and practice is perceived as a cycle, effective nursing care leading to good learning experiences, and effective education leading to effective nursing care. The paper indicates areas for further study and approaches to solving the problems.


10-Year Experience Using Inspira Implants: A Review with Personal Anecdote.
The article summarizes the author's experience with Inspira implants. They were first introduced into the European market in 2006. The advent of the Inspira range heralded a fundamental change in the way round implants were perceived. The comprehensive matrix, the form stability of the gels, along with sophisticated manufacturing of the shell placed them as a premium product for use in both aesthetic and reconstructive breast surgery. The same principles of precise tissue-based planning, developed for anatomical implants, were being adopted for use with Inspira, leading to more predictable outcomes with high levels of patient satisfaction.


Upper urinary tract lipoma: A case report.
Upper urinary tract (UUT) benign tumours are rare. We present a case of UUT lipoma in a 41-year-old man with left flank pain. A computed tomographic urography scan revealed an irregular thickening of the left renal collecting system wall extending from the upper calices to the renal pelvis. The diagnosis of UUT was made and the patient underwent a nephroureterectomy with bladder cuff excision, as standard treatment. However, macroscopic and histological examination revealed a lipomatous tumour with no sign of malignancy. To our knowledge this is the first reported case of its kind of a UUT managed first with a minimally invasive approach.


Atypical Antenatal Presentation of an Unusual Nonmucinous Papillary Variant of Giant Congenital Pulmonary Airway Malformation Masquerading as Congenital Diaphragmatic Hernia with Volvulus.
We report a case of a huge congenital pulmonary airway malformation (CPAM) that was referred as congenital diaphragmatic hernia (CDH). Initial ultrasound evaluation revealed a huge cystic lesion with septations, in the thorax, causing mediastinal shift and compression effects, suggesting the possibility of a thoracic lymphangioma, or bowel herniation with obstruction. A fetal magnetic resonance imaging reported possible bowel herniation through a posterior defect in the diaphragm, with volvulus, reinforcing the diagnosis of CDH. It was only on autopsy and subsequent histopathology examination that the diagnosis of a rare variant of CPAM-nonmucinous papillary type, could be made. To the best of our knowledge, a CPAM this huge has not been reported prenatally at this gestation. We recommend considering the potential diagnosis of CPAM in any thoracic cystic irrespective of its size or appearance.


Rational use of the fluoroquinolones.
The systemic fluoroquinolones (FQs) have recently been reported to be associated with significant side-effects in susceptible individuals. This has prompted the Food and Drug Administration (FDA) in the USA and the European Medicines Agency (EMA) to issue warnings regarding their use. The FQs should not be used for common bacterial infections, such as urinary tract infections, travellers' diarrhoea and upper and lower respiratory tract infections, unless it is not possible to use another oral agent. There are situations, however, in which these agents are not only effective, but their benefit outweighs the risk. These include the management of conditions such as acute prostatitis, typhoid fever, prosthetic joint infections, multidrug-resistant tuberculosis, certain hospital-acquired infections and situations where the organism is susceptible to FQs, which could then be administered orally. Alternatively, the patient would have to be admitted to hospital for parenteral therapy.


Slow clearance of human parvovirus B19 viremia following acute infection.
Parvovirus B19 is a common, clinically significant pathogen. Reassessment of the viral kinetics after acute infection showed that the virus is not rapidly cleared from healthy hosts, despite early resolution of symptoms. These findings challenge our current conception of the virus' pathogenesis and have implications for the management of the infection.


Childhood adversities and distress - The role of resilience in a representative sample.
While adverse childhood experiences have been shown to contribute to adverse health outcomes in adulthood, specifically distress and somatic symptoms, few studies have examined their joint effects with resilient coping style on adult adjustment. Hence, we aim to determine the association between resilient coping and distress in participants with and without reported childhood adversities. A representative German community sample (N = 2508) between 14-92 years (1334 women; 1174 men) was examined by the short form of the Childhood Trauma Questionnaire, the Brief Resilience Coping Scale, standardized scales of distress and somatoform symptoms. Childhood adversity was associated with reduced adjustment, social support and resilience. It was also strongly associated with increased distress and somatoform complaints. Resilient coping was not only associated with lower distress, it also buffered the effects of childhood adversity on distress. Our study corroborates the buffering effect of resilience in a representative German sample. High trait resilient subjects show less distress and somatoform symptoms despite reported childhood adversities in comparison to those with low resilient coping abilities.


Engineering selectivity of Cutibacterium acnes phages by epigenetic imprinting.
Cutibacterium acnes (C. acnes) is a gram-positive bacterium and a member of the human skin microbiome. Despite being the most abundant skin commensal, certain members have been associated with common inflammatory disorders such as acne vulgaris. The availability of the complete genome sequences from various C. acnes clades have enabled the identification of putative methyltransferases, some of them potentially belonging to restriction-modification (R-M) systems which protect the host of invading DNA. However, little is known on whether these systems are functional in the different C. acnes strains. To investigate the activity of these putative R-M and their relevance in host protective mechanisms, we analyzed the methylome of six representative C. acnes strains by Oxford Nanopore Technologies (ONT) sequencing. We detected the presence of a 6-methyladenine modification at a defined DNA consensus sequence in strain KPA171202 and recombinant expression of this R-M system confirmed its methylation activity. Additionally, a R-M knockout mutant verified the loss of methylation properties of the strain. We studied the potential of one C. acnes bacteriophage (PAD20) in killing various C. acnes strains and linked an increase in its specificity to phage DNA methylation acquired upon infection of a methylation competent strain. We demonstrate a therapeutic application of this mechanism where phages propagated in R-M deficient strains selectively kill R-M deficient acne-prone clades while probiotic ones remain resistant to phage infection.


Boron-Enhanced Growth of Micron-Scale Carbon-Based Nanowalls: A Route toward High Rates of Electrochemical Biosensing.
In this study, we have demonstrated the fabrication of novel materials called boron-doped carbon nanowalls (B:CNWs), which are characterized by remarkable electrochemical properties such as high standard rate constant (k°), low peak-to-peak separation value (ΔE) for the oxidation and reduction processes of the [Fe(CN)6]3-/4- redox system, and low surface resistivity. The B:CNW samples were deposited by the microwave plasma-assisted chemical vapor deposition (CVD) using a gas mixture of H2/CH4/B2H6 and N2. Growth results in sharp-edged, flat, and long CNWs rich in sp2 as well as sp3 hybridized phases. The achieved high values of k° (1.1 × 10-2 cm s-1) and ΔE (85 mV) are much lower compared to those of the glassy carbon or undoped CNWs. The enhanced electrochemical performance of the B:CNW electrode facilitates the simultaneous detection of DNA purine bases: adenine and guanine. Both separated oxidation peaks for the independent determination of guanine and adenine were observed by means of cyclic voltammetry or differential pulse voltammetry. It is worth noting that the determined sensitivities and the current densities were about 1 order of magnitude higher than those registered by other electrodes.


Generative modeling for renal microanatomy.
Generative adversarial networks (GANs) have received immense attention in the field of machine learning for their potential to learn high-dimensional and real data distribution. These methods do not rely on any assumptions about the data distribution of the input sample and can generate real-like samples from latent vector space based on unsupervised learning. In the medical field, particularly, in digital pathology expert annotation and availability of a large set of training data is costly and the study of manifestations of various diseases is based on visual examination of stained slides. In clinical practice, various staining information is required to improve the pathological diagnosis process. But when the sampled tissue to be examined is limited, the final diagnosis made by the pathologist is based on limited stain styles. These limitations can be overcome by studying the usability and reliability of generative models in the field of digital pathology. To understand the usability of the generative models, we synthesize in an unsupervised manner, high resolution renal microanatomical structures like renal glomerulus in thin tissue histology images using state-of-art architectures like Deep Convolutional Generative Adversarial Network (DCGAN) and Enhanced Super-Resolution Generative Adversarial Network (ESRGAN). Successful generation of such structures will lead to obtaining a large set of labeled data for further developing supervised algorithms for disease classification and understanding progression. Our study suggests while GAN is able to attain formalin fixed and paraffin embedded tissue image quality, GAN requires further prior knowledge as input to model intrinsic micro-anatomical details, such as capillary wall, urinary pole, nuclei placement, suggesting developing semi-supervised architectures by using these above details as prior information. Also, the generative models can be used to create an artificial effect of staining without physically tampering the histopathological slide. To demonstrate this, we use a CycleGAN network to transform Hematoxylin and eosin (H&E) stain to Periodic acid-Schiff (PAS) stain and Jones methenamine silver (JMS) stain to PAS stain. In this way GAN can be employed to translate different renal pathology stain styles when the relevant staining information is not available in the clinical settings.


Cognitive disorders in children's hydrocephalus.
Hydrocephalus is defined as an increase of volume of cerebrospinal fluid in the ventricular system of the brain. It develops as a result of cerebrospinal fluid flow disorder due to dysfunctions of absorption or, less frequently, as a result of the increase of its production. Hydrocephalus may lead to various cognitive dysfunctions in children. In order to determine cognitive functioning in children with hydrocephalus, the authors reviewed available literature while investigating this subject. The profile of cognitive disorders in children with hydrocephalus may include a wide spectrum of dysfunctions and the process of neuropsychological assessment may be very demanding. The most frequently described cognitive disorders within children's hydrocephalus include attention, executive, memory, visual, spatial or linguistic dysfunctions, as well as behavioral problems.


Nurses' attitudes to euthanasia: a review of the literature.
This article provides an overview of the scarce international literature concerning nurses' attitudes to euthanasia. Studies show large differences with respect to the percentage of nurses who are (not) in favour of euthanasia. Characteristics such as age, religion and nursing specialty have a significant influence on a nurse's opinion. The arguments for euthanasia have to do with quality of life, respect for autonomy and dissatisfaction with the current situation. Arguments against euthanasia are the right to a good death, belief in the possibilities offered by palliative care, religious objections and the fear of abuse. Nurses mention the need for more palliative care training, their difficulties in taking a specific position, and their desire to express their ideas about euthanasia. There is a need to include nurses' voices in the end-of-life discourse because they offer a contextual understanding of euthanasia and requests to die, which is borne out of real experience with people facing death.


Mechanism of universal conductance fluctuations.
Universal conductance fluctuations are usually observed in the form of aperiodic oscillations in the magnetoresistance of thin wires as a function of the magnetic field B. If such oscillations are completely random at scales exceeding ξ B , their Fourier analysis should reveal a white noise spectrum at frequencies below [Formula: see text]. Comparison with the results for 1D systems suggests another scenario: according to it, such oscillations are due to the superposition of incommensurate harmonics and their spectrum should contain discrete frequencies. An accurate Fourier analysis of the classical experiment by Washburn and Webb reveals a purely discrete spectrum in agreement with the latter scenario. However, this spectrum is close in shape to the discrete white noise spectrum whose properties are similar to a continuous one.


A Review of the Role of Solvents in Formation of High-Quality Solution-Processed Perovskite Films.
Recently, perovskite solar cells have attracted great attention because of their outstanding photovoltaic performance and ease of fabrication. High-quality perovskite films hold a key in getting highly efficient perovskite solar cells. Solution-processed fabrication technique is the most widely adopted for preparing perovskite films because of its low cost. In the solution-proceed perovskite films, solvents not only play the role of dissolving the solute but also participate in the crystallization of perovskite. In the one-step method, solvents play key roles in controlling morphology, widening process window, and achieving room-temperature crystallization of perovskite films. In addition, the solvents play important roles in controlling the nuclei/growth, suppressing volume expansion during the two-step method. Especially, the solvent can induce grain coarsening during the annealing process. A deep understanding of the multiplicity of roles during the formation of perovskite films will help understand the formation mechanism of perovskite films. Here, a systematic review on the progress in fabrication of high-quality perovskite films by making use of solvent to control the crystallization is presented. Meanwhile, we elucidate the key roles of solvent in the fabrication of high-quality perovskite films.


Synthesis and Characterization of Novel Acyl-Glycine Inhibitors of GlyT2.
It has been demonstrated previously that the endogenous compound N-arachidonyl-glycine inhibits the glycine transporter GlyT2, stimulates glycinergic neurotransmission, and provides analgesia in animal models of neuropathic and inflammatory pain. However, it is a relatively weak inhibitor with an IC50 of 9 μM and is subject to oxidation via cyclooxygenase, limiting its therapeutic value. In this paper we describe the synthesis and testing of a novel series of monounsaturated C18 and C16 acyl-glycine molecules as inhibitors of the glycine transporter GlyT2. We demonstrate that they are up to 28 fold more potent that N-arachidonyl-glycine with no activity at the closely related GlyT1 transporter at concentrations up to 30 μM. This novel class of compounds show considerable promise as a first generation of GlyT2 transport inhibitors.


Revised NMR data for incartine: an alkaloid from Galanthus elwesii.
Phytochemical studies on Galanthus elwesii resulted in the isolation of five alkaloids: incartine, hordenine, hippeastrine, 8-O-demethylhomolycorine and lycorine. The NMR data given previously for incartine were revised and completed by two-dimensional 1H-1H and 1H-13C chemical shift correlation experiments. In vitro studies on the bioactivity of incartine were carried out.


Serum cystatin C for assessment of glomerular filtration rate in pregnant and non-pregnant women. Indications of altered filtration process in pregnancy.
Serum cystatin C is believed to reflect the glomerular filtration rate (GFR) more closely than serum creatinine in many contexts and a reference interval for serum cystatin C in term pregnancy has been defined to enable its use also in pregnant women. However, serum cystatin C levels were not found to be decreased in term pregnancy, though GFR of low molecular mass substances is known to increase by at least 40% by the third trimester. The aim of this study was therefore to determine whether serum cystatin C is a reliable GFR marker also in pregnant women. GFR was determined by measurement of plasma clearance of iohexol in 48 previously healthy women in their third trimester and in 12 healthy nonpregnant women, and was compared with their serum levels of cystatin C and creatinine. Both serum cystatin C and creatinine levels were significantly related to GFR for both pregnant and non-pregnant women. However, the correlation between cystatin C and GFR was set at different levels for pregnant and nonpregnant women. Our results indicate a physiological difference between the filtration processes in kidneys of pregnant and non-pregnant women, whether it is size-dependent, configuration-dependent or charge-dependent. Nevertheless, serum cystatin C seems to reflect GFR reliably in both non-pregnant and pregnant, healthy and hypertensive women.


Human RNA helicase A is homologous to the maleless protein of Drosophila.
RNA helicase A is an abundant nuclear enzyme of HeLa cells that unwinds double-stranded RNA in a 3' to 5'direction (Lee, C. G., and Hurwitz, J. (1992) J. Biol. Chem. 267, 4398-4407). A complementary DNA (cDNA) clone expressing RNA helicase A was isolated by screening a human cDNA library with polyclonal antibodies produced against the purified protein. The deduced amino acid sequence from this clone showed that RNA helicase A is a member of the DEAH family of proteins thought to be helicases. Sequence comparison among all known proteins of the DEAH family revealed that the highest homology was between RNA helicase A and the maleless protein (MLE) of Drosophila. There was 49% identity and 85% similarity throughout the overall primary sequences of both proteins, suggesting that RNA helicase A is the human counterpart of Drosophila MLE. Polyclonal antibodies against Drosophila MLE recognized RNA helicase A in crude nuclear extracts of HeLa cells as well as the purified protein. A recombinant RNA helicase A containing 6 histidine residues at the NH2 terminus was expressed in Sf9 cells using a baculovirus vector. The protein isolated from insect cells and the enzyme purified from HeLa cells exhibited identical RNA helicase and RNA-dependent ATPase activities.


Adsorption of free steroids with charcoal-gelatin disks in radioimmunoassays.
The preparation of charcoal-gelatin disks and their use for removing free steroid in radioimmunoassays are described. Plasma concentrations of several steroids were determined using charcoal-gelatin disks or charcoal suspension and the results are compared. The advantages of using charcoal-gelatin disks are discussed.


Effect of soil moisture dynamics on dense nonaqueous phase liquid (DNAPL) spill zone architecture in heterogeneous porous media.
The amount, location, and form of NAPL in contaminated vadose zones are controlled by the spatial distribution of water saturation and soil permeability, the NAPL spill scenario, water infiltration events, and vapor transport. To evaluate the effects of these processes, we used the three-phase flow simulator STOMP, which includes a new permeability-liquid saturation-capillary pressure (k-S-P) constitutive model. This new constitutive model considers three NAPL forms: free, residual, and trapped. A 2-D vertical cross-section with five stratigraphic layers was assumed, and simulations were performed for seven cases. The conceptual model of the soil heterogeneity was based upon the stratigraphy at the Hanford carbon tetrachloride (CT) spill site. Some cases considered co-disposal of NAPL with large volumes of wastewater, as also occurred at the Hanford CT site. In these cases, the form and location of NAPL were most strongly influenced by high water discharge rates and NAPL evaporation to the atmosphere. In order to investigate the impact of heterogeneity, the hydraulic conductivity within the lower permeability layer was modeled as a realization of a random field having three different classes. For six extreme cases of 100 realizations, the CT mass that reached the water table varied by a factor of two, and was primarily controlled by the degree of lateral connectivity of the low conductivity class within the lowest permeability layer. The grid size at the top boundary had a dramatic impact on NAPL diffusive flux just after the spill event when the NAPL was present near the ground surface. NAPL evaporation with a fine grid spacing at the top boundary decreased CT mass that reached the water table by 74%, compared to the case with a coarse grid spacing, while barometric pumping had a marginal effect for the case of a continuous NAPL spill scenario considered in this work. For low water infiltration rate scenarios, the distribution of water content prior to a NAPL spill event decreased CT mass that reached the water table by 98% and had a significant impact on the formation of trapped NAPL. For all cases simulated, use of the new constitutive model that allows the formation of residual NAPL increased the amount of NAPL retained in the vadose zone. Density-driven advective gas flow from the ground surface controlled vapor migration in strongly anisotropic layers, causing NAPL mass flux to the lower layer to be reduced. These simulations indicate that consideration of the formation of residual and trapped NAPLs and dynamic boundary conditions (e.g., areas, rates, and periods of different NAPL and water discharge and fluctuations of atmospheric pressure) in the context of full three-phase flow are needed, especially for NAPL spill events at the ground surface. In addition, NAPL evaporation, density-driven gas advection, and NAPL vertical movement enhanced by water flow must be considered in order to predict NAPL distribution and migration in the vadose zone.


Eliminating bias in routine bioassay when there is an unknown time of intake.
Routine bioassay programmes sometimes find evidence of an unsuspected intake. If there were no workplace indicators of exposure or intake, it is necessary to assume a value for the time of intake. Under these circumstances, the International Commission on Radiological Protection (ICRP) continues to recommend using the midpoint of the interval between routine bioassay measurements (ICRP Publication 78, paragraph 106). The assumption of T/2 as the time of intake, where T is the interval between bioassay measurements, represents the expectation value of the time of intake, (t), assuming uniform probability of an intake at any given time. This assumption results in a modest bias, of the expectation value of the intake, (I), that would have been received by a population of workers who had uniform probability over time of intake. This underestimation leads to a negative or positive bias in dose estimates derived in this fashion. The bias is characterised for realistic, routine urinalysis programs for Pu, U and 3H, as well as for in vivo measurements of 125I, 131I and 137Cs. Simple numerical methods are presented for correcting the bias. The bias is greatest for radionuclides whose half-lives are short with respect to the interval between bioassay measurements. Since the primary concern is estimating intake rather than time, the assumed time of intake should be chosen as t(I) rather than T/2. The ICRP should consider revising some of the tables in its Publication 78 to reflect this.


FedADT: An Adaptive Method Based on Derivative Term for Federated Learning.
Federated learning is served as a novel distributed training framework that enables multiple clients of the internet of things to collaboratively train a global model while the data remains local. However, the implement of federated learning faces many problems in practice, such as the large number of training for convergence due to the size of model and the lack of adaptivity by the stochastic gradient-based update at the client side. Meanwhile, it is sensitive to noise during the optimization process that can affect the performance of the final model. For these reasons, we propose Federated Adaptive learning based on Derivative Term, called FedADT in this paper, which incorporates adaptive step size and difference of gradient in the update of local model. To further reduce the influence of noise on the derivative term that is estimated by difference of gradient, we use moving average decay on the derivative term. Moreover, we analyze the convergence performance of the proposed algorithm for non-convex objective function, i.e., the convergence rate of 1/nT can be achieved by choosing appropriate hyper-parameters, where n is the number of clients and T is the number of iterations, respectively. Finally, various experiments for the image classification task are conducted by training widely used convolutional neural network on MNIST and Fashion MNIST datasets to verify the effectiveness of FedADT. In addition, the receiver operating characteristic curve is used to display the result of the proposed algorithm by predicting the categories of clothing on the Fashion MNIST dataset.


"Why can't you control this?" How women's interactions with intimate partners define menopause and family.
In this article I explore women's discussions of the interactions that families have about menopause and, thus, attempt to broaden feminist knowledge of women's experiences of menopause within families. Data on which this article is based were collected in 61 in-depth interviews with menopausal women in a midwest state in 2001. Findings suggest that biomedical definitions of menopause are often reaffirmed within interactions between intimate partners. Thus, women reported negative familial interactions about menopause, as they were encouraged to define symptoms as problematic and seek medical treatment. Alternatively, some interviewees reported positive interactions about menopause, as a few partners helped them soothe symptoms and follow health regimens. Women interpreted these latter interactions as support or care, rather than surveillance or monitoring. The author concludes that familial interactions bolster dominant constructions of both menopause and family because, as menopause is discussed between intimate partners, definitions of gendered familial roles and responsibilities are cemented.


Ultrastructural changes of the skin induced by human leukocyte elastase and cathepsin G.
Human neutrophil elastase and cathepsin G at a concentration of 10(-6) M were found to attack various substrates when normal skin biopsy specimens were incubated at 37 degrees C for 1 h with either of these enzymes. Elastase damaged primarily hemidesmosomes, leading to the epidermal cleavage from the dermis, whereas cathepsin G damaged the membrane structures. Both these neutral proteinases were highly specific to basal lamina of blood vessels. This indicates that neutrophil elastase and neutrophil cathepsin G may play different roles in various skin diseases related to enhanced activity and infiltration of neutrophils.


Synthesis and biological analysis of a new curcumin analogue for enhanced anti-tumor activity in HepG 2 cells.
The aim of the present study was to investigate the apoptosis of human hepatocellular carcinoma cell line HepG 2 induced by a new curcumin analogue, GL63. HepG 2 cells were treated with increasing doses of GL63 and curcumin for 48 h. The proliferation of cells was detected with MTT. The apoptosis were examined by flow cytometry. The caspase-3 activity was detected by western blotting. ER calcium stores were assessed by the fluorescent calcium indicator fura-2/AM. The protein expression of ER stress pathway, GRP78, XBP-1, ATF-4 and CHOP were examined with western blotting. Growth inhibitory effect was observed for treatment with GL63 in a dose-dependent manner and with more potential than curcumin. GL63 at 20 microM induced significant apoptosis in HepG 2 cells. Furthermore, GL63 induced the ER stress response, up-regulation of CHOP, XBP-1, ATF-4 and GRP78 expression in a dose-dependent, while curcumin had no effect on ER stress. These results suggest that GL63 has more potent anti-tumor activity than curcumin, which is associated with activation of ER stress and induction of apoptosis in HepG 2 cells.


Cystic dystrophy of the duodenal wall developing in heterotopic pancreas: report of 9 cases.
Cystic dystrophy in heterotopic pancreas (CDHP), an uncommon but serious complication of dilatation of the ectopic pancreatic ducts of heterotopic pancreatic tissue, occurs most often in the second part of the duodenum. This disorder is difficult to diagnose and raises various therapeutic questions. The aim of this study was to evaluate the most useful procedures for investigating suspected CDHP and to consider late results after surgical treatment by pancreaticoduodenectomy (PD). This retrospective study concerned 9 patients who developed CDHP of the duodenal wall during an 18-year period (1983-2001). All patients were symptomatic and underwent PD (no postoperative deaths). Clinical presentation, imaging findings, pathological features, and follow-up were analyzed. All patients but one were male alcoholics (mean age, 48 years; range, 37-63 years). The clinical presentation was abdominal pain (n = 9) associated with vomiting (n = 6), jaundice (n = 2), and weight loss (n = 9). Upper endoscopy (n = 9) showed nonspecific inflammatory lesions with duodenal stenosis (n = 4). Retrospective analysis of computed tomographic findings (n = 9) studied specific signs of CDHP and nonspecific inflammatory changes in periduodenal space. Endoscopic ultrasonography (n = 4) and magnetic resonance cholangiopancreatography (n = 2) were the most useful investigations. Pathological findings in surgical specimens were multiple cysts located in the thickened duodenal wall (n = 9), ectopic pancreatic tissue (n = 7), fibrosis of the normal gland (n = 4), and adenocarcinoma in ectopic tissue (n = 1). During the follow-up period, 4 patients died 12, 16, 48, and 72 months after PD. The cause of death was independent of CDHP or PD, but related to persistent alcoholism in 2 cases involving chronic pancreatitis. In 1 case, the patient died of disseminated adenocarcinoma. The other 5 patients had a good result. Endoscopic ultrasonography and magnetic resonance pancreatography are the most useful investigations for the diagnosis of CDHP. Pancreaticoduodenectomy is justified after failure of medical treatment or endoscopic drainage. Late results after PD are dependent on alcoholic consumption when CDHP is associated with chronic pancreatitis.


[Histological characteristics of the prostate in men who receive re-TURP for benign prostatic hyperplasia and their clinical significance].
To investigate the pathohistological characteristics of the prostate tissues in patients who receive a second TURP and to evaluate their clinical significance. We collected surgical specimens from 50 cases of TURP (the control group) and another 50 cases of re-TURP (the re-TURP group), detected the expressions of CD34, vascular endothelial growth factor (VEGF) and androgen receptor (AR) in the prostate tissues by immunohistochemistry (S-P), and determined microvessel density (MVD) and the expressions of VEGF and AR. We performed statistical analyses on the results obtained from the specimens of the control group as well as from those of the first and second operations of the re-TURP group. VEGF and AR expressed in all the specimens. The expressions of VEGF and AR and MVD were significantly higher in the re-TURP group than in the controls (P < 0.05), but showed no significant differences between the first and second operations in the re-TURP group (P > 0.05). Positive correlations were found between the expressions of AR and VEGF, VEGF and MVD, and AR and MVD (r = 0.650, 0.705 and 0.525, P < 0.05). Increased AR, VEGF and MVD in the prostatic tissues may be one of the important causes of recurrence of BPH after TURP, and could be considered as the risk factors for postoperative recurrence and targeted indicators for preventive measures.


Crucial roles of sucrose and microRNA399 in systemic signaling of P deficiency: a tale of two team players?
MicroRNAs (miRNAs) have been recognized as important regulators in plant response to nutrient deficiencies. Of particular interest is the discovery that miR399 functions systemically in the maintenance of phosphate (Pi) homeostasis in response to external Pi fluctuation. Recent studies have further implicated both miR399 and sugars (mainly sucrose) as potential signal molecules in the shoot-to-root communication of phosphorus (P) status. Given that both miR399 and sucrose are transported via the phloem, their potential interaction (or cross-talk) along the signaling pathway is especially appealing for further exploration. In this mini-review, we highlight recent progress in unraveling crucial roles of both sucrose and miR399 in P-deficiency signaling. In particular, we further discuss recent findings that photosynthetic carbon (C) assimilation and subsequent partitioning, by overriding signaling of low external Pi, act as checkpoints upstream of miR399 for the onset of a systemic P-deficiency status.


Ixolaris, a novel recombinant tissue factor pathway inhibitor (TFPI) from the salivary gland of the tick, Ixodes scapularis: identification of factor X and factor Xa as scaffolds for the inhibition of factor VIIa/tissue factor complex.
Saliva of the hard tick and Lyme disease vector, Ixodes scapularis, has a repertoire of compounds that counteract host defenses. Following sequencing of an I scapularis salivary gland complementary DNA (cDNA) library, a clone with sequence homology to tissue factor pathway inhibitor (TFPI) was identified. This cDNA codes for a mature protein, herein called Ixolaris, with 140 amino acids containing 10 cysteines and 2 Kunitz-like domains. Recombinant Ixolaris was expressed in insect cells and shown to inhibit factor VIIa (FVIIa)/tissue factor (TF)-induced factor X (FX) activation with an inhibitory concentration of 50% (IC(50)) in the picomolar range. In nondenaturing gel, Ixolaris interacted stoichiometrically with FX and FXa but not FVIIa. Ixolaris behaves as a fast-and-tight ligand of the exosites of FXa and gamma-carboxyglutamic acid domainless FXa (des-Gla-FXa), increasing its amidolytic activity. At high concentration, Ixolaris attenuates the amidolytic activity of FVIIa/TF; however, in the presence of DEGR-FX or DEGR-FXa (but not des-Gla-DEGR-FXa), Ixolaris becomes a tight inhibitor of FVIIa/TF as assessed by recombinant factor IX (BeneFIX) activation assays. This indicates that FX and FXa are scaffolds for Ixolaris in the inhibition of FVIIa/TF and implies that the Gla domain is necessary for FVIIa/TF/Ixolaris/FX(a) complex formation. Additionally, we show that Ixolaris blocks FXa generation by endothelial cells expressing TF. Ixolaris may be a useful tool to study the structural features of FVIIa, FX, and FXa, and an alternative anticoagulant in cardiovascular diseases.


Dispersion properties of nonradiating configurations: finite-difference time-domain modeling.
A finite-difference time-domain (FDTD) numerical analysis is used to demonstrate that a toroidal solenoid, coaxial with an electric dipole, is a remarkable nonradiating configuration. It can be used to measure the dielectric permittivity of any ambient matter. It becomes a directional radiator at an interface between two dielectric media, depositing energy in the material with the highest polarizability.


TROP-2 expression in papillary thyroid carcinoma: Potential Diagnostic Utility.
TROP-2 is a type I transmembrane glycoprotein which is over-expressed in various malignancies, and is related to epithelial cell adhesion molecule (EpCAM), also called TROP-1, gp40, and KSA. In this study, we evaluated TROP-2 expression in papillary thyroid carcinoma (PTC) and compared it to other thyroid neoplastic and non-neoplastic lesions. Immunohistochemical (IHC) evaluation for TROP-2 was performed on 137 thyroid fine needle aspiration (FNA) cell blocks (CB) which included classic PTC (64), follicular variant PTC (FVPTC) (10), anaplastic thyroid carcinoma (AC) (2), medullary carcinoma (MC) (8), follicular neoplasms (FN) (8), Hurthle cell neoplasms (HCN) (9), follicular lesion of uncertain significance (FLUS) (12), and benign thyroid nodule (BTN) (24). IHC for TROP-2 expression was also performed on 331 BTN and malignant tumor tissue sections in tissue microarray (TMA). Membranous staining in >5% of tumor cells was considered positive. TROP-2 stained 61 of 64 PTC CB, 7 of 10 FVPTC CB, and 9 of 12 FLUS CB. All other cases were negative for TROP-2. TROP-2 showed a sensitivity of 95.31% and specificity of 89% for classic PTC in FNA CB. In TMA samples, TROP-2 stained 54 of 60 classic PTC cases and hence showed a high sensitivity and specificity. All BTN in CB and TMA were negative. We conclude that TROP-2 is a highly sensitive and specific IHC marker for identifying classic PTC. TROP-2 may play an important role in diagnosing classic PTC, especially in equivocal cases. This study also identifies a strong role for TROP-2 in separating PTC from BTN.


A meta-analysis of weekend admission and surgery for aortic rupture and dissection.
We performed a meta-analysis to determine whether weekend admission and surgery for ruptured abdominal/thoracic aortic aneurysm (RAAA/RTAA) and acute aortic dissection (AAD) is associated with increased mortality. MEDLINE and EMBASE were searched from January 1946 to December 2016 using PubMed and OVID. Eligible studies were prospective or retrospective, comparative or cohort studies enrolling patients admitting or undergoing surgery for RAAA/RTAA/AAD and reporting mortality after weekend (including holiday) versus weekday admission/surgery. Our search identified 11 studies including a total of 166,195 patients. A pooled analysis of 13 adjusted odds ratios (ORs), one adjusted hazard ratio, and one unadjusted OR from all 11 studies demonstrated a statistically significant 32% increase in mortality with weekend admission/surgery (OR, 1.32; 95% confidence interval (CI), 1.20 to 1.45; p < 0.00001). Despite possible publication bias disadvantageous to weekend admission/surgery based on funnel plot asymmetry, adjustment for the asymmetry using the trim-and-fill method did not alter the significant association of weekend admission/surgery with increased mortality (OR, 1.21; 95% CI, 1.09 to 1.34; p = 0.0006). In conclusion, weekend admission/surgery for ruptured abdominal/thoracic aortic aneurysm and acute aortic dissection (AAD) may be associated with increased mortality.


The Role of the Oligodendrocyte Lineage in Acute Brain Trauma.
An acute brain injury is commonly characterized by an extended cellular damage. The post-injury process of scar formation is largely determined by responses of various local glial cells and blood-derived immune cells. The role of astrocytes and microglia have been frequently reviewed in the traumatic sequelae. Here, we summarize the diverse contributions of oligodendrocytes (OLs) and their precursor cells (OPCs) in acute injuries. OLs at the lesion site are highly sensitive to a damaging insult, provoked by Ca2+ overload after hyperexcitation originating from increased levels of transmitters. At the lesion site, differentiating OPCs can replace injured oligodendrocytes to guarantee proper myelination that is instrumental for healthy brain function. In contrast to finally differentiated and non-dividing OLs, OPCs are the most proliferative cells of the brain and their proliferation rate even increases after injury. There exist even evidence that OPCs might also generate some type of astrocyte beside OLs. Thereby, OPCs can contribute to the generation and maintenance of the glial scar. In the future, detailed knowledge of the molecular cues that help to prevent injury-evoked glial cell death and that control differentiation and myelination of the oligodendroglial lineage will be pivotal in developing novel therapeutic approaches.


Genetic analysis of variation in lifespan using a multiparental advanced intercross Drosophila mapping population.
Considerable natural variation for lifespan exists within human and animal populations. Genetically dissecting this variation can elucidate the pathways and genes involved in aging, and help uncover the genetic mechanisms underlying risk for age-related diseases. Studying aging in model systems is attractive due to their relatively short lifespan, and the ability to carry out programmed crosses under environmentally-controlled conditions. Here we investigate the genetic architecture of lifespan using the Drosophila Synthetic Population Resource (DSPR), a multiparental advanced intercross mapping population. We measured lifespan in females from 805 DSPR lines, mapping five QTL (Quantitative Trait Loci) that each contribute 4-5 % to among-line lifespan variation in the DSPR. Each of these QTL co-localizes with the position of at least one QTL mapped in 13 previous studies of lifespan variation in flies. However, given that these studies implicate >90 % of the genome in the control of lifespan, this level of overlap is unsurprising. DSPR QTL intervals harbor 11-155 protein-coding genes, and we used RNAseq on samples of young and old flies to help resolve pathways affecting lifespan, and identify potentially causative loci present within mapped QTL intervals. Broad age-related patterns of expression revealed by these data recapitulate results from previous work. For example, we see an increase in antimicrobial defense gene expression with age, and a decrease in expression of genes involved in the electron transport chain. Several genes within QTL intervals are highlighted by our RNAseq data, such as Relish, a critical immune response gene, that shows increased expression with age, and UQCR-14, a gene involved in mitochondrial electron transport, that has reduced expression in older flies. The five QTL we isolate collectively explain a considerable fraction of the genetic variation for female lifespan in the DSPR, and implicate modest numbers of genes. In several cases the candidate loci we highlight reside in biological pathways already implicated in the control of lifespan variation. Thus, our results provide further evidence that functional genetics tests targeting these genes will be fruitful, lead to the identification of natural sequence variants contributing to lifespan variation, and help uncover the mechanisms of aging.


See One, Do One, Order One: a study protocol for cluster randomized controlled trial testing three strategies for implementing motivational interviewing on medical inpatient units.
General medical hospitals provide care for a disproportionate share of patients who abuse or are dependent upon substances. This group is among the most costly to treat and has the poorest medical and addiction recovery outcomes. Hospitalization provides a unique opportunity to identify and motivate patients to address their substance use problems in that patients are accessible, have time for an intervention, and are often admitted for complications related to substance use that renders hospitalization a "teachable moment." This randomized controlled trial will examine the effectiveness of three different strategies for integrating motivational interviewing (MI) into the practice of providers working within a general medical inpatient hospitalist service: (1) a continuing medical education workshop that provides background and "shows" providers how to conduct MI (See One); (2) an apprenticeship model involving workshop training plus live supervision of bedside practice (Do One); and (3) ordering MI from the psychiatry consultation-liaison (CL) service after learning about it in a workshop (Order One). Thirty providers (physicians, physician assistants, nurses) will be randomized to conditions and then assessed for their provision of MI to 40 study-eligible inpatients. The primary aims of the study are to assess (1) the utilization of MI in each condition; (2) the integrity of MI when providers use it on the medical units; and (3) the relative costs and cost-effectiveness of the three different implementation strategies. If implementation of Do One and Order One is successful, the field will have two alternative strategies for supporting medical providers' proficient use of brief behavioral interventions, such as MI, for medical inpatients who use substances problematically. Clinical Trials.gov ( NCT01825057 ).


The peptidomimetic Vasotide targets two retinal VEGF receptors and reduces pathological angiogenesis in murine and nonhuman primate models of retinal disease.
Blood vessel growth from preexisting vessels (angiogenesis) underlies many severe diseases including major blinding retinal diseases such as retinopathy of prematurity (ROP) and aged macular degeneration (AMD). This observation has driven development of antibody inhibitors that block a central factor in AMD, vascular endothelial growth factor (VEGF), from binding to its receptors VEGFR-1 and mainly VEGFR-2. However, some patients are insensitive to current anti-VEGF drugs or develop resistance, and the required repeated intravitreal injection of these large molecules is costly and clinically problematic. We have evaluated a small cyclic retro-inverted peptidomimetic, D(Cys-Leu-Pro-Arg-Cys) [D(CLPRC)], and hereafter named Vasotide, that inhibits retinal angiogenesis by binding selectively to the VEGF receptors VEGFR-1 and neuropilin-1 (NRP-1). Delivery of Vasotide via either eye drops or intraperitoneal injection in a laser-induced monkey model of human wet AMD, a mouse genetic knockout model of the AMD subtype called retinal angiomatous proliferation (RAP), and a mouse oxygen-induced model of ROP decreased retinal angiogenesis in all three animal models. This prototype drug candidate is a promising new dual receptor inhibitor of the VEGF ligand with potential for translation into safer, less-invasive applications to combat pathological angiogenesis in retinal disorders.


ST-segment elevation in the early repolarization syndrome, idiopathic ventricular fibrillation, and the Brugada syndrome: cellular and clinical linkage.
ST-segment elevation in a structurally normal heart is associated with an electrocardiographic (ECG) J wave, which can be observed in the early repolarization syndrome (ERS), idiopathic ventricular fibrillation (VF), and the Brugada syndrome. Animal studies have demonstrated that the J wave is the consequence of a transmural voltage gradient resulting from an Ito-mediated action potential notch (spike and dome) in epicardium but not endocardium. Ito-mediated spike and dome morphology predisposes loss or depression of the dome in epicardium, leading to ST-segment elevation. Despite the fact that 3 clinical syndromes share many common ECG features, their clinical consequences are remarkably different. The ERS is a benign ECG finding characterized by a distinct J wave and ST segment in left precordial leads V4 through V6. In contrast, idiopathic VF and the Brugada syndrome, characterized by a J wave and ST-segment elevation in the inferior and right precordial leads, respectively, are the leading causes for sudden cardiac death in young Southeast Asian males. The underlying mechanism for such a difference in clinical consequences among these syndromes is due to a difference in Ito density and Ito-mediated epicardial spike and dome. When Ito is prominent, complete loss of the dome may occur due to either a decrease in inward currents or an increase in outward currents, leading to phase 2 reentry capable of initiating VF as in idiopathic VF and the Brugada syndrome. When Ito is relatively small as in the ERS, partial depression of the dome occurs without the development of phase 2 reentry.


Contrast Enhancement for Portal Imaging in Nanoparticle-Enhanced Radiotherapy: A Monte Carlo Phantom Evaluation Using Flattening-Filter-Free Photon Beams.
Our team evaluated contrast enhancement for portal imaging using Monte Carlo simulation in nanoparticle-enhanced radiotherapy. Dependencies of percentage contrast enhancement on flattening-filter (FF) and flattening-filter-free (FFF) photon beams were determined by varying the nanoparticle material (gold, platinum, iodine, silver, iron oxide), nanoparticle concentration (3-40 mg/mL) and photon beam energy (6 and 10 MV). Phase-space files and energy spectra of the 6 MV FF, 6 MV FFF, 10 MV FF and 10 MV FFF photon beams were generated based on a Varian TrueBeam linear accelerator. We found that gold and platinum nanoparticles (NP) produced the highest contrast enhancement for portal imaging, compared to other NP with lower atomic numbers. The maximum percentage contrast enhancements for the gold and platinum NP were 18.9% and 18.5% with a concentration equal to 40 mg/mL. The contrast enhancement was also found to increase with the nanoparticle concentration. The maximum rate of increase of contrast enhancement for the gold NP was equal to 0.29%/mg/mL. Using the 6 MV photon beams, the maximum contrast enhancements for the gold NP were 79% (FF) and 78% (FFF) higher than those using the 10 MV beams. For the FFF beams, the maximum contrast enhancements for the gold NP were 53.6% (6 MV) and 53.8% (10 MV) higher than those using the FF beams. It is concluded that contrast enhancement for portal imaging can be increased when a higher atomic number of NP, higher nanoparticle concentration, lower photon beam energy and no flattening filter of photon beam are used in nanoparticle-enhanced radiotherapy.


The combination of non-contrast abbreviated MRI and alpha foetoprotein has high performance for hepatocellular carcinoma screening.
This study aimed to compare two abbreviated MRI (AMRI) protocols to complete MRI for HCC detection: non-contrast (NC)-AMRI without/with alpha foetoprotein (AFP) and dynamic contrast-enhanced (Dyn)-AMRI. This retrospective single-center study included 351 patients (M/F: 264/87, mean age: 57y) with chronic liver disease, who underwent MRI for HCC surveillance between 2014 and 2020. Two reconstructed AMRI sets were obtained based on complete MRI: NC-AMRI (T2-weighted imaging (WI) + diffusion-WI) and Dyn-AMRI (T2-WI + dynamic T1-WI) and were assessed by 2 radiologists who reported all suspicious lesions, using LI-RADS/adapted LI-RADS classification. The reference standard was based on all available patient data. Inter-reader agreement was assessed and MRI diagnostic performance was compared to the reference standard. The reference standard demonstrated 83/351 HCC-positive patients (prevalence: 23.6%, median size: 22 mm, and positive MRIs: 83/631). Inter-reader agreement was substantial for all sets. Sensitivities of Dyn-AMRI and complete MRI (both 92.8%) were similar, higher than NC-AMRI (72.3%, p < 0.001). Specificities were not different between sets. NC-AMRI + AFP (92.8%) had similar sensitivity to Dyn-AMRI and complete MRI. In patients with small size HCCs (≤ 2 cm), sensitivities of Dyn-AMRI (85.3%) and complete MRI (88.2%) remained similar (p = 0.564), also outperforming NC-AMRI (52.9%, p < 0.05). NC-AMRI + AFP had similar sensitivity (88.2%) to Dyn-AMRI and complete MRI (p = 0.706 and p = 1, respectively). Dyn-AMRI has similar diagnostic performance to complete MRI for HCC detection, while both outperform NC-AMRI, especially for small size HCCs. NC-AMRI + AFP demonstrates similar sensitivity to Dyn-AMRI and complete MRI. Due to the low sensitivity of ultrasound for hepatocellular screening, new screening methods are needed. Abbreviated MRI (AMRI) is a candidate, especially non-contrast AMRI with serum alpha foetoprotein as the acquisition time is low, without the need for contrast medium injection. • Dynamic contrast-enhanced abbreviated MRI using extracellular gadolinium-based contrast agent and complete MRI have similar diagnostic performance for hepatocellular carcinoma detection in an at-risk population. • Non-contrast abbreviated MRI with alpha foetoprotein has similar diagnostic performance to dynamic contrast-enhanced abbreviated MRI and complete MRI, including when considering small size hepatocellular carcinoma ≤ 2 cm. • Non-contrast abbreviated MRI and dynamic contrast-enhanced abbreviated MRI can be performed in 7 and 10 min, excluding patient setup time.


Nursing management of diabetes insipidus.
Diabetes insipidus is seen most frequently in neurosurgical patients. The transient form is more common and usually subsides prior to discharge. Permanent DI is seen in patients with extensive damage in the hypothalamic area. Treatment of either form of DI is usually with a preparation of vasopressin. Nursing assessements and interventions are crucial to a successful outcome in patients with this disorder. Health teaching for patients with permanent DI is an integral part of the nursing responsibility.